Induction of MAPK- and ROS-dependent autophagy and apoptosis in gastric carcinoma by combination of romidepsin and bortezomib

Proteasome inhibitors and histone deacetylase (HDAC) inhibitors can synergistically induce apoptotic cell death in certain cancer cell types but their combinatorial effect on the induction of autophagy remains unknown. Here, we investigated the combinatorial effects of a proteasome inhibitor, bortezomib, and an HDAC inhibitor, romidepsin, on the induction of apoptotic and autophagic cell death in gastric carcinoma (GC) cells. Isobologram analysis showed that low nanomolar concentrations of bortezomib/romidepsin could synergistically induce killing of GC cells. The synergistic killing was due to the summative effect of caspase-dependent intrinsic apoptosis and caspase-independent autophagy. The autophagic cell death was dependent on the activation of MAPK family members (ERK1/2 and JNK), and generation of reactive oxygen species (ROS), but was independent of Epstein-Barr virus infection. In vivo, bortezomib/romidepsin also significantly induced apoptosis and autophagy in GC xenografts in nude mice. This is the first report demonstrating the potent effect of combination of HDAC and proteasome inhibitors on the induction of MAPK- and ROS-dependent autophagy in addition to caspase-dependent apoptosis in a cancer type.published_or_final_versio

Reactivation of Epstein-Barr virus lytic cycle by histone deacetylase inhibitors

Epstein-Barr virus (EBV) is closely associated with certain lymphoid and epithelial malignancies such as Burkitt lymphoma, nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC). In the tumor cells, the virus persists in a tight latency, expressing a limited number of latent proteins. Reactivation of EBV lytic cycle from latency leads to expression of many more viral lytic proteins which may provide potential therapeutic targets for the EBV-associated cancers. Histone deacetylase (HDAC) inhibitors belong to an emerging class of anti-cancer agents which work through acetylation of different histone and non-histone proteins in cancer cells. Our previous work showed that various pan-HDAC inhibitors, which inhibit eleven HDAC isoforms, can preferentially reactivate EBV lytic cycle in EBV-positive epithelial rather than lymphoid cancers and mediate enhanced killing of EBV-positive NPC and GC cells through augmentation of apoptotic cell death. Recently, we found that a selective class I HDAC inhibitor, romidepsin, can potently induce EBV lytic cycle in NPC and GC cells and confer susceptibility of the induced cells to killing by an anti-viral agent, ganciclovir, in vitro and in vivo. The reactivation of EBV lytic cycle by romidepsin is related to the inhibition of HDAC-1, -2 and -3 isoforms and the activation of PKC-. Interestingly, our current findings suggest that acetylation of non-histone proteins might also play a role in the regulation of EBV lytic cycle upon HDAC inhibition. In this review, we discuss our recent findings on the mechanisms of EBV lytic cycle reactivation and propose possible strategies in using HDAC inhibitors for the treatment of EBV-associated cancers.published_or_final_versio

Immunology-based control framework for multi-jointed redundant manipulators

Artificial Immune System (AIS) has recently been actively researched with a number of emerging engineering applications that has capitalized from its characteristics including self-organization, distributive control, knowledge mapping and fault tolerance. This paper reports the development of an AIS paradigm for the distributive control of a multi-jointed, redundant manipulator. Traditionally, manipulator control is achieved by analytical solutions. By adopting a multiagent-based control paradigm, a multi-jointed manipulator can be thought of as a group of separately controlled agents. In this paper, we investigate the viability of a multiagent immunology-based control framework for the trajectory control of a multi-jointed redundant manipulator.published_or_final_versio

The canonical word order myth: investigating a processing-typological puzzle in the Cantonese double object construction

PosterThe frequency of canonicity (frequent, structurally basic and/or pragmatically neutral) word orders is often associated with easier processing, while syntactic alternatives usually incur complexity and processing difficulty (Hawkins, 2004; Ellis, 2002; Cook et al., 2009). In this paper we show that the canonical double-object construction (DOC, a) in Cantonese (VO with head-final NPs) is difficult to process in that incremental increases in the complexity of the direct object (DO) increase reading time (RT) and reduce recall accuracy relative to syntactic alternatives, and induce greater avoidance of the DOC in elicited production. We hypothesize that this is because the canonical word order involves processing-demanding center-embedding ...postprin

Amplitude Zeroes in Collinear Processes or What Is Left from a Factorizable 2d Model in Higher Dimensions

We show that for collinear processes, i.e. processes where the incoming and outgoing momenta are aligned along the same line, the S-matrix of the tree level 2+1 dimensional Thirring model factorizes: any S - matrix element is a product of $2\rightarrow 2$ elements. In particular this means nullification of all collinear $2 \rightarrow n$ amplitudes for $n > 2$.Comment: latex , 8 pp., 2 fig. not include

Malignancies in Chinese patients with neurofibromatosis type 1

published_or_final_versio

Bortezomib combines with suberoylanilide hydroxamic acid (SAHA) to synergistically induce caspase-dependent apoptosis and blocks SAHA's activation of EBV lytic cycle in nasopharyngeal carcinoma

Poster Session 1 - Vaccines and Anti-Viral Therapeutics: no. 3.13Histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), could induce Epstein-Barr virus (EBV) lytic cycle and apoptosis in EBV-positive nasopharyngeal carcinoma (NPC) cells. In this study, we investigated the effects of combining a proteasome inhibitor, bortezomib, with SAHA in the treatment of NPC cells. Synergistic killing of a panel of EBV-positive NPC cells upon treatment with various combinations of bortezomib (0, 7.5, 15, 30, 60 and 120 nM) and SAHA (0, 0.625, 1.25, 2.5, 5 and 10 uM) was demonstrated by MTT assay and isobologram analysis. The synergistic killing was due to apoptosis as demonstrated by markedly increased sub-G1, annexin V-positive and TUNEL-positive cell populations. Strong proteolytic cleavage of PARP, caspase-3, -7 and -9 and increased reactive oxygen species …postprin

ABA-mediated proline synthesis in cowpea leaves exposed to water deficiency and rehydration

peer reviewe